Palladium-Catalyzed One-Pot Reaction of Hydrazones, Dihaloarenes, and Organoboron Reagents: Synthesis and Cytotoxic Activity of 1,1-Diarylethylene Derivatives

Article abstract of DOI:10.1021/acs.joc.5b00880

A new three-component assembly reaction between N-tosylhydrazones, dihalogenated arenes, and boronic acids or boronate esters was developed, producing highly substituted 1,1-diarylethylenes in good yields. The two C-C bonds formed through this coupling ha

Full text of DOI:10.1021/acs.joc.5b00880

Article
pubs.acs.org/joc
Palladium-Catalyzed One-Pot Reaction of Hydrazones, Dihaloarenes,
and Organoboron Reagents: Synthesis and Cytotoxic Activity of
1,1-Diarylethylene Derivatives
Maxime Roche,† Salim Mmadi. Salim,† Jerome Bignon,‡ Helene Levaique,‡ Jean-Daniel Brion,†
́
̂
́
̀
Mouad Alami,*,† and Abdallah Hamze*,†
†Universite
Chimie Ther
́
Paris-Sud, CNRS, BioCIS−UMR 8076, Equipe Labellisee Ligue Contre le Cancer, LabEx LERMIT, Laboratoire de
́
́
apeutique, Faculte de Pharmacie, rue J.-B. Clement, F−92296 Chatenay-Malabry, France
́
́
̂
‡Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, avenue de la Terrasse, F-91198 Gif sur Yvette, France
S
* Supporting Information
ABSTRACT: A new three-component assembly reaction
between N-tosylhydrazones, dihalogenated arenes, and boronic
acids or boronate esters was developed, producing highly sub-
stituted 1,1-diarylethylenes in good yields. The two C−C
bonds formed through this coupling have been catalyzed by a
single Pd-catalyst in a one-pot fashion. It is noted that the
one-pot pinacol boronate cross-coupling reaction generally
provides products in high yields, offers an expansive substrate
scope, and can address a broad range of aryl, styrene, vinyl, and
heterocyclic olefinic targets. The scope of this one-pot
coupling has been also extended to the synthesis of the 1,1-
diarylethylene skeleton of the natural product ratanhine. The new compounds were evaluated for their cytotoxic activity, and this
allowed the identification of compound 4ab that exhibits excellent antiproliferative activity in the nanomolar concentration range
against HCT116 cancer cell lines.
olefins.6 Since then, important transformations such as cross-
INTRODUCTION
■
couplings,7 oxidative cross-couplings8 or domino reactions have
A fascinating myriad of adventurous and unique palladium-
catalyzed transformations are found frequently to be key steps in
been emerging.9 On the basis of our long-standing experience,
in the chemistry of 1,1-diarylethylenes10 combined with our
target-oriented synthesis, affording complex natural products
efforts to discover novel isocombretastatin A-4 derivatives,11 as
and pharmacologically active compounds.1 Thus, the desire for
promising antineoplastic agents (Scheme 1),12 led us to study a
quick and easy access to complex structures is still a major task
series of Pd-13 or Cu14-catalyzed cross-coupling reactions of
for the organic chemist in the 21st century. On the other hand,
concerns related to pollution or sustainability are increasing
worldwide. In this light, the development of new simple synthetic
methods allowing time and cost savings while reducing waste and
N-tosylhydrazones with different partners to generate a library of
potentially actives compounds.
In connection with these studies, and in order to increase the
diversity of new potential active compounds, we envisaged to
hazardous byproducts is an essential and major challenge. In this
create two distinct C−C bonds in a one-step reaction using one
context, palladium cascade reactions are particularly attractive
and have generated considerable interest over the years in com-
parison to traditional stepwise methodologies. It represents a
powerful tool capable of rapid generation of diverse and complex
catalyst, following the strategy depicted in Scheme 1. The first
C−C bond will be created through a carbene migratory insertion
strategy and the second one by a Suzuki−Miyaura coupling
molecules from readily available simple starting materials.2
reaction. In comparison to the previous synthesis of similar com-
pounds, which needs 4 to 5 steps including 1,2 addition, oxida-
Cascade reaction has various advantages over classical step-
tion, Wittig reaction, coupling, and deprotection (Scheme 1A),12
wise strategy, such as operational simplicity and environmental
friendliness.3 During the past decade, particular attention has
this strategy will lead to a time-saving and a reduction of the
number of steps. We have chosen the Suzuki−Miyaura cross-
been given to autotandem catalysis, in which a single catalyst
activates mechanistically distinct reactions in a single reactor.4
coupling reaction, because it is nowadays one of the most
common C−C bond forming methods in organic synthesis, due
N-Tosylhydrazones have been proven to be very useful for the
in situ generation of nonstabilized diazo compounds through
Bamford−Stevens reaction.5 Recently, Barluenga et al. reported a
palladium-catalyzed cross-coupling reaction between N-tosylhy-
drazones and aryl halides for the preparation of polysubstituted
to (i) mild reaction conditions, (ii) both academic and industrial
Received: April 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00880
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Scheme 1. (A) Synthesis of Isocombretastatin A-4 Derivative 4af; (B) This Work: One-Pot Pd-Catalyzed Reactions Involving
Hydrazones, Dihaloarenes, and Boronic Acid Derivatives
interest for this reaction, and (iii) its tolerance toward funct-
ional groups. In addition, organoboron reagents display many
advantages including stability, no toxicity, easy handling,
and commercial availability.15 Here we describe a strategy that
directly addresses this gap in synthetic methodology and pres-
ents a single-flask, catalytic two C−C bond formation from
N-tosylhydrazones, dihalogenated arenes, and organoboron
reagents.
cross-coupling (entries 4−5). Adding 5 equiv of water for the
second coupling led to a significant improvement in the yield,
furnishing compound 4a in a 60% yield, whereas with 50 or 100
equiv of water the yield decreased up to 15% (entries 5−6).
Water and base are required to activate the boronic acid leading
to the formation of the tetrahedral anion [ArB(OH)3]−.16
A further investigation of various solvents revealed that cyclopentyl
methyl ether (CPME) is more efficient than dioxane or toluene
(entries 4, 7 and 8). Finally, from the optimized result of entry 8,
we further changed the palladium source (entries 9−10), com-
pared to other sources of palladium, Pd(OAc)2 leads to the
formation of expected compound 4a, with a good yield of 84%.
This represents an average of 92% yield for both steps of this
coupling process. As a result, the combination of Pd(OAc)2/
SPhos and LiO-t-Bu in refluxing CPME for the first step and then
phenylboronic acid, K3PO4·H2O and water (5 equiv) for the
second step was fixed, as optimal conditions.
We next explored the scope of this reaction with various
hydrazones, dihaloarenes, and boronic acids, the results are
summarized in Table 2. The reaction is general with respect to
N-tosylhydrazone partners, both electron-rich and electron-poor
hydrazones (compounds 4b−d) have been efficiently coupled.
N-Tosylhydrazones derived from aliphatic ketone provided good
yield (4h). However, the coupling with N-tosylhydrazone of
chromanone gives a slightly lower yield (4e). To gauge the
performance of this catalytic system, the substrate scope with
respect to boronic acid partners (compounds 4f−4k) has been
examined. When styryl boronic acid was used as a new coupling
partner, unfortunately, no trace of 4k was detected in the crude
reaction mixture. Finally, the third component of this reaction,
dihaloarene, was studied. Switching the halide atom from para-
position to meta-position on the aryl ring of 2 did not influence
the yields (compounds 4l,m). However, no product was ob-
tained with 1-chloro-2-iodobenzene as coupling partner (4o).
Interestingly, our catalytic system was also effective with dihalo-
heterocycle, despite the fact that the reaction conditions had
RESULTS AND DISCUSSION
■
This study might seem to be trivial, since we can think that the
conditions of coupling for the first and the second steps are
known separately. But the challenge is to find the best conditions
able to catalyze simultaneously and efficiently the two couplings
in a one-pot manner. In the search for effective conditions, the
reaction was carried out with N-tosylhydrazone 1a, 1-choloro-4-
iodobenzene 2a and phenylboronic acid 3a with various
palladium sources, ligands, solvents, and additives to form olefin
4a, as summarized in Table 1. Initially, for the formation of the
first C−C bond between hydrazone 1a and 1-chloro-4-
iodobenzene 2a, we used Pd2dba3/XPhos as a catalytic system,
LiO-t-Bu as a base at reflux in dioxane, following reported
conditions (entry 1).6 After completion of the reaction as judged
by TLC, we added potassium phosphate tribasic monohydrate
(K3PO4·H2O), and phenylboronic acid for the second coupling.
Accordingly, the desired product 4a was obtained in an en-
couraging yield of 25% (Table 1, entry 1). If Xphos and Sphos
ligands catalyze the first coupling effectively, Sphos was found to
be more powerful for the second Suzuki−Miyaura coupling,
affording the required product 4a in a 50% yield (entry 2).
Switching from K3PO4·H2O to anhydrous K3PO4 did not
produce the desired product, instead, the intermediate 1-chloro-
4-(1-(p-tolyl)vinyl)benzene was obtained as the major product
accompanied by the 1,1-biphenyl as side product (entry 3).
This result clearly suggests the role played by water for the
second reaction and led us to examine its effect as additive in this
B
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a
Table 1. Optimization of the Pd-Catalyzed Migratory Insertion/Suzuki−Miyaura Coupling One-Pot Reaction
b
b
d
entry
[Pd]/ligand
solvent
base
H2O (equiv)
4a yield (%)
c
1
2
3
4
5
6
7
8
9
10
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
Pd2dba3·CHCl3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
CPME
CPME
CPME
K3PO4·H2O
K3PO4·H2O
K3PO4
0
25
50
0
e
0
traces
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
5
60
15
12
60
73
65
84
50
100
5
5
PdCl2(MeCN)2
Pd(OAc)2
5
5
a
First step: Reactions were performed with hydrazone 1a (1.1 equiv), dihaloarene 2a (1 equiv, 1 mmol), LiO-t-Bu (2.4 equiv), Pd source (4 mol %),
b
ligand (8 mol %), in 8 mL of solvent at reflux. Second step: phenylboronic acid (1.5 equiv), H2O, and base (3 equiv) were added after completion
of the first step. Xphos was used as a ligand instead of SPhos. Yield of product 4a. 1-Chloro-4-(1-(p-tolyl)vinyl)benzene was obtained as the major
c
d
e
product accompanied by the 1,1-biphenyl side product.
never been optimized. Thus, an indole, a pyridine, or a quinolone
core can be included in the final products (4p−r).
focus on the synthesis of examples that did not work using
boronic acid as the coupling partner. Notably, in these condi-
tions, ortho-dihaloarene substrate was coupled efficiently,
furnishing 4t in a satisfactory yield, whereas no product was
obtained when using boronic acid as coupling partner (compare
4o in Table 2, with 4t in Table 4). A similar trend was observed
when achieving the one pot reaction with styrylboronic ester
instead of boronic acid derivative (see Table 2, compound 4k,
and Table 4, compound 4x). Finally, heterocyclic (4v) or
vinylboronate (4w) can also participate in the coupling with
good yield.
To highlight the power and the usefulness of this Pd-catalyzed
cascade reaction, we synthesized several analogues of isocom-
bretastatin A-4 (compounds 4y−4ae) in order to explore their
cytotoxic activity. Thus, using commercially available starting
materials, in one step and with only one purification, we obtained
a small library of compounds with potential antiproliferative
activity. Next, a further deprotection of compound 4ae using
TBAF furnished product 4af (Table 4), one of our lead com-
pounds, with antiproliferative activity against a panel of cancer
cell lines.12
To increase the scope of our one-pot reaction and find solution
for coupling with 2-phenylvinylboronic acid (compound 4k),
or for the formation of sterically hindered products such as
compound 4o, we thought to use pinacol boronic esters instead
of boronic acids. Under normal laboratory conditions, boronic
acids exist as a mixture of monomer, dimer, and boroxine.17 This
drawback can be overcome by the use of boronate esters which
are air and water stable and exist only in a monomeric form in
nature. Further advantages of boronate esters include ease of
preparation and practicality of purification by column
chromatography.18
Initially, we first replaced phenylboronic acid 3a by phenyl-
boronic ester 5a in our previous protocol (Table 3, entry 1).
Under these conditions, we obtained 4a in a promising 50%
yield. We have previously noticed in this one pot reaction that the
water played a critical role for complete conversion of starting
materials. Thus, in the presence of water (50 equiv) 4a was
isolated in a 62% yield (entry 3). Screening with respect to the
solvent revealed that CPME could be replaced by dioxane,
providing 4a in a similar yield (entry 5). The yield could be
further improved by using potassium hydroxide as a base in place
of potassium phosphate (entry 7). Finally, we confirmed that
the use of 50 equiv of water were optimal, while using 100 equiv
furnished a lower yield of 4a (entry 8). With the optimized
conditions in hand, the scope of this reaction was then explored
(Table 4). Compound 4s was obtained in a good yield, similar to
that obtained with boronic acid (Table 2, 4l). In a further
exploration of our boronic ester based protocol, we decided to
Thus, 4af was obtained in a two-step sequence (2 purifications
by column chromatography) in a 52% overall yield, whereas in
the precedent work (Scheme 1A), this molecule was synthesized
in 5 steps (5 purifications by column chromatography) in an
18% overall yield. This result demonstrates the usefulness of our
protocol, which should accelerate the discovery of promising
cytotoxic agents.
To illustrate the usefulness of the cross-coupling method, we
embarked in the synthesis of the 1,1-diarylethylene skeleton of
C
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a b
,
Table 2. Scope of Pd-Catalyzed Migratory Insertion/Suzuki−Miyaura Coupling One-Pot Reaction
a
First step: Reactions were performed with hydrazone 1 (1.1 equiv), dihaloarene 2 (1 equiv, 1 mmol), LiO-t-Bu (2.4 equiv), Pd(OAc)2 (4 mol %),
SPhos (8 mol %), in 8 mL of CPME at reflux. Second step: boronic acid 3 (1.5 equiv), H2O (5 equiv), and K3PO4·H2O (3 equiv) were added after
b
completion of the first step. Yield of product 4.
the natural product ratanhine. The total synthesis of this mole-
cule, extracted from Ratanhiae radix,19 was reported by Burke
and co-workers using an iterative cross-coupling strategy with a
trivalent N-methyliminodiacetic acid (MIDA) ligand.20
The dihaloarene partner 2i was synthesized according to
Burke procedure from 2-iodo-5-methoxyphenol 6 through an
alkylation and bromination sequence (Scheme 2, part A).20 The
pinacol boronate 5k was synthesized in a two steps sequence
from the benzofuran 8 involving an iridium catalyzed C−H
borylation coupling (Scheme 2, part B).21 Because of its
instability, compound 5k was used directly for the next coupling
sequence without purification.
D
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a
concentration required to decrease cell growth by 50%) of
isoCA-4 analogs are listed in Table 5. The results clearly reveal
that the size of the substituent at the 3′-position of isoCA-4
skeleton plays a critical role in cell growth inhibition. Introduc-
tion of a benzene or pyrazole rings at the 3′-position (com-
pounds 4y and 4aa) resulted in a significant decrease in
cytotoxicity, probably owing to steric considerations and absence
of hydrogen bond. Compound 4z having a pyridine group at this
position was evaluated and showed promising antiproliferative
activity, with GI50 = 300 nM. Finally the best antiproliferative
activity was obtained with compound 4ab having a small cyclo-
propylvinyl group on position 3′ of 1,1-diarylethylene which
exhibited significant antiproliferative activities, with GI50 values
of 70 nM against HCT116 cells. This structure−activity relation-
ship study demonstrate that the replacement of the hydrox-
ymethyl moiety of 4af by a cyclopropyl moiety led only to slight
decrease of the growth inhibition.
Table 3. Coupling with Phenylboronic Acid Pinacol Ester
a
b
c
entry
solvent
base
H2O (equiv)
4a yield (%)
1
2
3
4
5
6
7
8
CPME
CPME
CPME
toluene
dioxane
dioxane
dioxane
dioxane
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K2CO3
5
50
33
62
34
70
76
89
43
none
50
50
50
50
KOH
50
KOH
100
a
CONCLUSION
First step: reactions were performed with hydrazone 1a (1.1 equiv),
■
dihaloarene 2a (1 equiv, 1 mmol), LiO-t-Bu (2.4 equiv), Pd source
(4 mol %), ligand (8 mol %), in 8 mL of solvent at reflux. Second
In summary, a one-pot catalytic reaction of N-tosylhydrazones,
dihaloarenes, and organoboron reagents into substituted
1,1-diarylethylenes is described. This sequence, which requires
only one palladium catalyst, allows the formation of two distinct
C−C bonds in a one-pot fashion. One bond was created through
an aryl migratory insertion on palladium carbene specie and the
other by a Suzuki−Miyaura coupling. Moderate to excellent
yields were obtained with a wide range of the three coupling
partners. Two different conditions are disclosed, one for boronic
acids and the other for pinacol boronates. As a general rule, yields
are higher and scope is broader with conditions developed for
the coupling of pinacol boronate. This one pot reaction was
successfully applied to the synthesis of a library of potential or
proven cytotoxic agents.
b
step: phenylboronic acid pinacol ester 5a (1.5 equiv), additive, and
base (3 equiv) were added after completion of the first step. Yield of
product 4a.
c
For the synthesis of N-tosylhydrazones 1, we need first to find
an appropriate protective group on the phenol function of 1,
which should be compatible with our coupling protocol achieved
under basic conditions. In addition, its deprotection should be
orthogonal to the MOM-protective group present on 2i. To this
end, a screening of various protective groups has been realized
using a simplified model for the coupling between 2j and pro-
tected hydrazones 1n−t (Scheme 3).
The coupling of aryl iodide 2j with unprotected (R = H) or
protected (R = Acyl or silyl group) hydrazones 1o−s under our
standard protocol were, however, unsuccessful. Ultimately, the
use of para-methoxybenzyl group (PMB) provided the coupling
product 4ag with a 60% yield (Scheme 3).
Having defined the best protective group, we next turned to
perform the synthesis of the building block 1u. This latter was
synthesized in a good overall yield from the commercially
available acetophenone 10 in three steps including benzylation,
Suzuki−Miyaura coupling,22 and hydrazone formation (Scheme 3,
bottom part).
Finally, we performed the one pot coupling reaction between
hydrazone 1u, dihaloarene 2i, and pinacol boronate 5k under our
standard conditions. Accordingly, the desired product 4ah was
obtained with a promising 45% yield (Scheme 4). To access
the formal synthesis of ratanhine, it remains to achieve the
deprotection of the PMB group and the installation of the
benzoyl group. Different known protocols were tested to achieve
the deprotection of the PMB group of 4ah. However, no traces of
the desired compound were detected using as reagents DDQ,23
CAN24 or AgSbF6.25 Only traces of the desired product were
observed accompanied by degradation of starting material 4ah.
Even if this step remains difficult to perform, we demonstrated
the potential of our methodology in the synthesis of the
1,1-diaryethylene framework of natural product ratanhine.
Biological Results. New 1,1-diarylethylenes 4 having a
trimethoxyphenyl unit (4y−4ac) as well as compound 4ah were
evaluated for their in vitro cytotoxicity against HCT116 cell lines
(human colon tumor) using isocombretastatin A-4 (isoCA-4)
as the reference compound (Table 5). The GI50 values (drug
EXPERIMENTAL SECTION
■
General Methods. Solvent peaks were used as reference values, with
1
CDCl3 at 7.26 ppm for H NMR and 77.16 ppm for 13C NMR, with
1
CD3COCD3 at 2.05 ppm for H NMR and 29.84 ppm for 13C NMR.
Chemical shifts δ are given in ppm, and the following abbreviations
are used: singlet (s), doublet (d), doublet of doublet (dd), triplet (t),
multiplet (m) and broad singlet (bs). Reaction courses and product
mixtures were routinely monitored by TLC on silica gel, and
compounds were visualized with phosphomolybdic acid/Δ, anisalde-
hyde/Δ, or vanillin/Δ. Flash chromatography was performed using
silica gel 60 (40−63 mm, 230−400 mesh) at medium pressure
(200 mbar). Fluorobenzene was used as received, dioxane, dichloromethane,
cyclohexane and tetrahydrofuran were dried using the procedures described
in D. Perrin Purification of Laboratory Chemicals.26 Organic extracts
were, in general, dried over MgSO4 or Na2SO4. High-resolution mass
spectra were recorded with the aid of a MicrOTOF-Q II. All products
1
reported showed H and 13C NMR spectra in agreement with the
assigned structures.
Typical Pd-Catalyzed One-Pot Catalysis of N-Tosylhydra-
zones with Dihaloarenes and Boronic Acids. A 20 mL round-
bottom flask with a condenser under an argon atmosphere was charged
with N-tosylhydrazone (1.1 equiv, 1.1 mmol), Pd(OAc)2 (9 mg,
4 mol %), SPhos (32 mg, 8 mol %), dihaloarene (1.0 equiv, 1 mmol) and
LiO-t-Bu (192 mg, 2.4 equiv, 2.4 mmol). Then 8 mL of CPME was
added via syringe at room temperature. The flask was put into a
preheated oil bath and stirred at reflux for 2 h (or until completion of the
reaction as judged by TLC). Then boronic acid (1.5 equiv), K3PO4·H2O
(690 mg, 3 equiv, 3 mmol) and water (0.09 mL, 5 equiv, 5 mmol) were
added and reflux was continued for 4 h (or until completion of the
reaction as judged by TLC). The crude reaction mixture was allowed to
cool to room temperature. EtOAc was added to the mixture, which was
filtered through Celite. The solvents were evaporated under reduce
E
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Table 4. Scope of the Pd-Catalyzed Migratory Insertion/Suzuki−Miyaura Coupling Cascade Reaction Using Pinacol Boronate
a b
,
Esters
a
First step: Reactions were performed with hydrazone 1 (1.1 equiv), dihaloarene 2 (1 equiv, 1 mmol), LiO-t-Bu (2.4 equiv), Pd(OAc)2 (4 mol %),
SPhos (8 mol %), in 8 mL of dioxane at reflux. Second step: boronic ester 5 (1.5 equiv), H2O (50 equiv), and KOH (3 equiv) were added after
b
c
d
completion of the first step. Yield of product 4. K2CO3 was used instead of KOH. 4af was obtained from 4ae by using TBAF in THF.
pressure and the crude residue was purified by chromatography on
silica gel.
evaporated under reduce pressure and the crude residue was purified by
chromatography on silica gel.
Typical Pd-Catalyzed One-Pot Catalysis of N-Tosylhydra-
zones with Dihaloarenes and Boronic Acid Pinacol Esters. A
20 mL round-bottom flask with a condenser under an argon atmosphere
was charged with N-tosylhydrazone (1.1 equiv, 1.1 mmol), Pd(OAc)2
(9 mg, 4 mol %), SPhos (32 mg, 8 mol %), dihaloarene (1.0 equiv,
1 mmol) and LiO-t-Bu (192 mg, 2.4 equiv, 2.4 mmol). Then 8 mL of
dioxane was added via syringe at room temperature. The flask was put
into a preheated oil bath and stirred at reflux for 1 h 45 min (or until
completion of the reaction as judged by TLC). Then boronic ester
(1.5 equiv), KOH (168 mg, 3 equiv, 3 mmol) and water (0.9 mL,
50 equiv, 50 mmol) were added, and reflux was continued for 18 h (or
until completion of the reaction as judged by TLC). The crude reaction
mixture was allowed to cool to room temperature. EtOAc was added
to the mixture, which was filtered through Celite. The solvents were
4-(1-(p-Tolyl)vinyl)-1,1-biphenyl (4a). Flash chromatography on
silica gel (Cyclohexane) afforded 230 mg of 4a (0.84 mmol, yield 84%).
White solid, mp 200−202 °C. TLC Rf = 0.63 (Cyclohexane, SiO2). IR
(neat) 1477, 1508, 1456, 1404, 1263, 1076 cm−1. 1H NMR (300 MHz,
CDCl3) δ (ppm) 7.69−7.61 (m, 2H, HAr), 7.61−7.55 (m, 2H, HAr),
7.51−7.33 (m, 5H, HAr), 7.33−7.27 (m, 2H, HAr), 7.21−7.16 (m, 2H,
HAr), 5.50 (d, J = 1.3 Hz, 1H, CH), 5.47 (d, J = 1.3 Hz, 1H, CH),
2.40 (s, 3H, Ar−CH3). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm)
149.6 (C), 140.9 (C), 140.8 (C), 140.6 (C), 138.7 (C), 137.7 (C), 129.0
(2CH), 128.9 (2CH), 128.8 (2CH), 128.4 (2CH), 127.5 (CH), 127.2
(2CH), 127.0 (2CH), 113.8 (CH2), 21.3 (CH3). HRMS (APCI)
(M + H)+ m/z calcd for C21H19 271.1487 found 271.1495.
4-(1-(4-Methoxyphenyl)vinyl)-1,1-biphenyl (4b). Chromatography
on silica gel (AcOEt/Cyclohexane, 0/100 to 1/99) afforded 188 mg of
F
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Scheme 2. Synthesis of Building Blocks 2i and 5k
Scheme 3. Top: Optimization of the Coupling between Hydrazone 1n−t and Aryl Iodide 2j; Bottom: Synthesis of Building
Block 1u
Scheme 4. Pd-Catalyzed One Pot Reaction for the Synthesis of 4ah
4b (0.66 mmol, yield 66%). White solid, mp 163−164 °C. TLC Rf = 0.22
(Cyclohexane, SiO2). IR (neat) 1606, 1508, 1471, 1249, 1112,
1030 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.67−7.55
(m, 4H, HAr), 7.50−7.40 (m, 4H, HAr), 7.37−7.30 (m, 3H, HAr), 6.91 (d,
J = 8.9 Hz, 2H, HAr), 5.44 (d, J = 1.3 Hz, 1H, CH), 5.43 (d, J = 1.3 Hz,
1H, CH), 3.85 (s, 3H, Ar−OCH3). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 159.5 (C), 149.3 (C), 140.9 (2C), 140.6 (C), 134.1
(C), 129.6 (2CH), 128.9 (2CH), 128.8 (2CH), 127.5 (CH), 127.2
(2CH), 127.0 (2CH), 113.7 (2CH), 113.1 (CH2), 55.5 (CH3). HRMS
(APCI) (M + H)+ m/z calcd for C21H19O 287.1430 found 287.1435.
4-(1-([1,1-Biphenyl]-4-yl)vinyl)benzonitrile (4c). Chromatography
on silica gel (DCM/Cyclohexane, 0/100 to 30/70) afforded 135 mg of
4c (0.48 mmol, yield 48%). White solid, mp 149−150 °C. TLC Rf = 0.22
(DCM/Cyclohexane, 10/90, SiO2). IR (neat) 2360 (CN stretch),
1
1647, 1488, 1456, 1418, 1275 cm−1. H NMR (300 MHz, CDCl3) δ
(ppm) 7.71−7.55 (m, 6H, HAr), 7.53−7.42 (m, 4H, HAr), 7.42−7.31 (m,
3H, HAr), 5.66 (d, J = 0.6 Hz, 1H, CH), 5.56 (d, J = 0.6 Hz, 1H, 
CH). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 148.5 (C), 146.2 (C),
141.3 (C), 140.6 (C), 139.2 (C), 132.3 (2CH), 129.1 (2CH), 129.0
(2CH), 128.7 (2CH), 127.7 (CH), 127.3 (2CH), 127.2 (2CH),
119.0 (C), 116.8 (CH2), 111.6 (C). HRMS (APCI) (M + H)+ m/z calcd
for C21H16N 282.1283 found 282.1299.
4-(1-(3-Fluoro-4-methoxyphenyl)vinyl)-1,1-biphenyl (4d). Chro-
matography on silica gel (EtOAc/Cyclohexane, 0/100 to 1/99) afforded
182 mg of 4d (0.60 mmol, yield 60%). White solid, mp 145−147 °C.
TLC Rf = 0.24 (Cyclohexane, SiO2). IR (neat) 1519, 1276, 1260,
G
DOI: 10.1021/acs.joc.5b00880
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a
Table 5. Cytotoxic Activity of Selected Substituted 1,1-Diarylethylenes 4, against HCT-116 Cells
a
b
HCT116 human colon carcinoma cells. GI50: compound concentration required to decrease cell growth by 50% following 72 h treatment with the
c
tested drug; values represent the average SD of three experiments. NA = not active.
1076 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.69−7.57 (m, 4H,
HAr), 7.52−7.33 (m, 5H), 7.20−7.08 (m, 2H, HAr), 6.95 (t, J = 8.6 Hz,
1H, HAr), 5.47 (d, J = 0.9 Hz, 1H, CH), 5.45 (d, J = 1.0 Hz, 1H, 
CH), 3.93 (s, 3H, Ar−OCH3). 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 152.2 (C, d, J = 243.8 Hz), 148.4 (C), 147.5 (C, d, J = 10.9 Hz),
140.9 (C), 140.8 (C), 140.2 (C), 134.8 (d, J = 6.3 Hz), 128.9 (2CH),
128.8 (2CH), 127.5 (CH), 127.2 (2CH), 127.1 (2CH), 124.2 (CH, d,
J = 3.0 Hz), 116.1 (CH, d, J = 18.8 Hz), 114.0 (CH2), 113.1 (d, J = 1.2
Hz), 56.5 (CH3). HRMS (ESI) (M + H)+ m/z calcd for C21H18OF
305.1342 found 305.1339.
4-([1,1-Biphenyl]-4-yl)-2H-chromene (4e). Chromatography on
silica gel (DCM/Cyclohexane, 0/100 to 2/98) afforded 127 mg of 4e
(0.45 mmol, yield 45%). Yellow solid, mp 88−90 °C. TLC Rf = 0.27
(Cyclohexane, SiO2). IR (neat) 1601, 1483, 1462, 1447, 1302, 1223,
1115 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.70−7.60 (m, 4H,
HAr), 7.52−7.33 (m, 5H, HAr), 7.23−7.16 (m, 1H, HAr), 7.10 (dd, J = 7.7,
1.6 Hz, 1H, HAr), 6.97−6.85 (m, 2H, HAr), 5.87 (t, J = 4.0 Hz, 1H, 
CH), 4.89 (d, J = 4.0 Hz, 2H, O−CH2−CH). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 155.0 (C), 140.8 (2C), 137.4 (C), 137.0 (C), 129.4
(CH), 129.2 (2CH), 129.0 (2CH), 127.5 (CH), 127.2 (2CH), 127.2
(2CH), 126.0 (CH), 123.8 (C), 121.3 (CH), 120.1 (CH), 116.4 (CH),
65.4 (CH2). HRMS (APCI) (M + H)+ m/z calcd for C21H17O 285.1279
found 285.1275.
(2CH), 126.4 (CH), 126.1 (CH), 125.8 (CH), 125.6 (CH), 113.9
(CH2), 21.3 (CH3). HRMS (APCI) (M + H)+ m/z calcd for C25H21
321.1638 found 321.1642.
4-(1-(4-Fluorophenyl)vinyl)-4′-methoxy-1,1-biphenyl (4g). Chro-
matography on silica gel (Et2O/Cyclohexane, 0/100 to 1/99) afforded
250 mg of 4g (0.82 mmol, yield 82%). White solid, mp 143−144 °C.
TLC Rf = 0.31 (Cyclohexane, SiO2). IR (neat) 1502, 1316, 1288, 1249,
1158 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.57 (d, J = 7.4 Hz,
2H, HAr), 7.54 (d, J = 7.1 Hz, 2H, HAr), 7.42−7.32 (m, 4H, HAr), 7.06 (d,
J = 8.8 Hz, 2H, HAr), 7.00 (d, J = 8.9 Hz, 2H, HAr), 5.50 (d, J = 1.0 Hz,
1H, CH), 5.42 (d, J = 1.0 Hz, 1H, CH), 3.87 (s, 3H, Ar−OCH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 162.5 (C, d, J = 245.3 Hz),
159.3 (C), 148.7 (C), 140.3 (C), 139.6 (C), 137.6 (C, d, J = 3.8 Hz),
133.2 (C), 130.0 (2CH, d, J = 8.3 Hz), 128.6 (2CH), 128.0 (2CH),
126.5 (2CH), 115.1 (2CH, d, J = 21.0 Hz), 114.3 (2CH), 114.0 (CH2),
55.4 (CH3). HRMS (APCI) (M + H)+ m/z calcd for C21H18FO
305.1336 found 305.1338.
4-(3,3-Dimethylbut-1-en-2-yl)-4′-methoxy-1,1-biphenyl (4h).
Chromatography on silica gel (AcOEt/Cyclohexane, 0/100 to 1/99)
afforded 173 mg of 4h (0.65 mmol, yield 65%). White solid, mp 108−
109 °C. TLC Rf = 0.24 (Cyclohexane, SiO2). IR (neat) 1522, 1496,
1360, 1287, 1040 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.55 (d,
J = 8.8 Hz, 2H, HAr), 7.48 (d, J = 8.3 Hz, 2H, HAr), 7.20 (d, J = 8.3 Hz,
2H, HAr), 6.98 (d, J = 8.8 Hz, 2H, HAr), 5.21 (d, J = 1.6 Hz, 1H, CH),
4.82 (d, J = 1.6 Hz, 1H, CH), 3.86 (s, 3H, Ar−OCH3), 1.16 (s, 9H,
tBu). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 159.8 (C), 159.2 (C),
142.1 (C), 138.9 (C), 133.7 (C), 129.5 (2CH), 128.2 (2CH), 125.7
(2CH), 114.3 (2CH), 111.8 (CH2), 55.5 (CH3), 36.3 (C), 29.9 (3CH3).
HRMS (APCI) (M + H)+ m/z calcd for C19H23O 267.1743 found
267.1755.
2-(4-(1-(p-Tolyl)vinyl)phenyl)naphthalene (4f). Chromatography
on silica gel (Cyclohexane) afforded 239 mg of 4f (0.75 mmol, yield
75%). White solid, mp 146−147 °C. TLC Rf = 0.15 (Heptane, SiO2).
1
IR (neat) 1607, 1501, 1330, 1119, 1017 cm−1. H NMR (300 MHz,
CDCl3) δ (ppm) 8.10 (bs, 1H), 7.99−7.84 (m, 3H, HAr), 7.80 (dd, J =
8.6, 1.7 Hz, 1H, HAr), 7.72 (d, J = 8.5 Hz, 2H, HAr), 7.58−7.46 (m, 4H,
HAr), 7.33 (d, J = 8.1 Hz, 2H, HAr), 7.21 (d, J = 7.9 Hz, 2H, HAr), 5.53 (d,
J = 1.0 Hz, 1H, CH), 5.50 (s, 1H, CH), 2.42 (s, 3H, Ar−CH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 149.7 (C), 140.9 (C),
140.5 (C), 138.7 (C), 138.2 (C), 137.7 (C), 133.8 (C), 132.8 (C), 129.1
(2CH), 128.9 (2CH), 128.6 (CH), 128.4 (3CH), 127.8 (CH), 127.2
Isopropyl 4′-(1-(p-tolyl)vinyl)-[1,1-biphenyl]-4-carboxylate (4i).
Chromatography on silica gel (AcOEt/Cyclohexane, 0/100 to 1/99)
afforded 227 mg of 4i (0.64 mmol, yield 64%). Yellow solid, mp 157−
159 °C. TLC Rf = 0.11 (Cyclohexane, SiO2). IR (neat) 1711 (CO
H
DOI: 10.1021/acs.joc.5b00880
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1
stretch), 1608, 1511, 1273, 1179, 1098 cm−1. H NMR (300 MHz,
CDCl3) δ (ppm) 8.12 (d, J = 8.4 Hz, 2H, HAr), 7.68 (d, J = 8.4 Hz, 2H,
HAr), 7.60 (d, J = 8.3 Hz, 2H, HAr), 7.45 (d, J = 8.3 Hz, 2H, HAr), 7.28 (d,
J = 8.2 Hz, 2H, HAr), 7.17 (d, J = 7.9 Hz, 2H, HAr), 5.48 (s, 2H, CH2),
5.29 (hept, J = 6.3 Hz, 1H, CH−(CH3)2), 2.39 (s, 3H, Ar−CH3), 1.40
(d, J = 6.2 Hz, 6H, CH−(CH3)2). 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm) 166.1 (C), 149.5 (C), 145.1 (C), 141.7 (C), 139.4 (C), 138.5
(C), 137.8 (C), 130.2 (2CH), 129.9 (C), 129.1 (2CH), 129.0 (2CH),
128.3 (2CH), 127.1 (2CH), 126.9 (2CH), 114.1 (CH2), 68.5 (CH),
22.1 (2CH3), 21.3 (CH3). HRMS (ESI) (M + H)+ m/z calcd for
C25H25O2 357.1855 found 357.1857.
1382, 1243, 1177 cm−1. H NMR (300 MHz, CD3COCD3) δ (ppm)
7.85−7.81 (m, 1H, HAr), 7.55 (d, J = 8.9 Hz, 2H, HAr), 7.40 (d, J = 9.2
Hz, 2H, HAr), 7.27 (d, J = 8.2 Hz, 2H, HAr), 7.20 (d, J = 1.6 Hz, 1H, HAr),
7.18−7.12 (m, 2H, HAr), 6.97 (d, J = 8.8 Hz, 2H, HAr), 5.39 (s, 2H, 
CH2), 3.88 (s, 3H, Ar−OCH3), 3.80 (s, 3H, N−CH3), 2.33 (s, 3H, Ar−
CH3). 13C{1H} NMR (75 MHz, CD3COCD3) δ (ppm) 159.0 (C),
152.2 (C), 140.4 (C), 138.3 (C), 138.1 (C), 134.3 (C), 129.6 (2CH),
129.0 (4CH), 127.9 (CH), 127.9 (C), 127.0 (C), 123.4 (CH), 120.1
(CH), 117.2 (C), 115.1 (2CH), 112.4 (CH2), 110.2 (CH), 55.5 (CH3),
33.0 (CH3), 21.2 (CH3). HRMS (ESI) (M + H)+ m/z calcd for
C25H24NO 354.1858 found 354.1859.
2-Phenyl-5-(1-(p-tolyl)vinyl)pyridine (4q). Chromatography on
silica gel (AcOEt/Cyclohexane, 0/100 to 1/99) afforded 145 mg of
4q (0.54 mmol, yield 54%). White solid, mp 78−79 °C. TLC Rf = 0.26
(AcOEt/Cyclohexane, 2/98, SiO2). IR (neat) 1588, 1474, 1455, 1362,
1106 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 8.75 (d, J = 0.9 Hz,
1H, HAr), 8.06 (d, J = 6.9 Hz, 2H, HAr), 7.79−7.66 (m, 2H, HAr), 7.57−
7.40 (m, 3H, HAr), 7.29 (d, J = 8.1 Hz, 2H, HAr), 7.20 (d, J = 8.0 Hz, 2H,
HAr), 5.57 (s, 1H, CH), 5.54 (s, 1H, CH), 2.42 (s, 3H, Ar−CH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 156.6 (C), 149.3 (CH),
146.8 (C), 139.2 (C), 138.2 (C), 137.7 (C), 136.4 (CH), 135.7 (C),
129.3 (2CH), 129.1 (CH), 128.9 (2CH), 128.1 (2CH), 127.0 (2CH),
119.8 (CH), 114.9 (CH2), 21.3 (CH3). HRMS (ESI) (M + H)+ m/z
calcd for C20H18N 272.1439 found 272.1439.
1-(4′-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)vinyl)-[1,1-biphenyl]-
4-yl)ethanone (4j). Chromatography on silica gel (AcOEt/Cyclohexane,
1/99 to 10/90) afforded 182 mg of 4j (0.51 mmol, yield 51%). White
solid, mp 165−166 °C. TLC Rf = 0.30 (AcOEt/Cyclohexane, 20/80,
SiO2). IR (neat) 1680 (CO stretch), 1604, 1504, 1267, 1248,
1123 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 8.04 (d, J = 8.5 Hz,
2H, HAr), 7.71 (d, J = 8.5 Hz, 2H, HAr), 7.60 (d, J = 8.4 Hz, 2H, HAr), 7.45
(d, J = 8.4 Hz, 2H, HAr), 6.92−6.89 (m, 1H, HAr), 6.87−6.84 (m, 2H,
HAr), 5.44 (d, J = 1.1 Hz, 1H, CH), 5.42 (d, J = 1.1 Hz, 1H, CH), 4.28
(bs, 4H, O−CH2−CH2−O), 2.64 (s, 3H, CO−CH3). 13C{1H} NMR
(75 MHz, CDCl3) δ (ppm) 197.8 (C), 148.9 (C), 145.4 (C), 143.6 (C),
143.3 (C), 141.7 (C), 139.2 (C), 136.0 (C), 134.8 (C), 129.1 (4CH),
127.2 (2CH) 127.1 (2CH), 121.6 (CH), 117.3 (CH), 117.1 (CH),
113.8 (CH2), 64.6 (CH2), 64.5 (CH2), 26.8 (CH3). HRMS (ESI)
(M + H)+ m/z calcd for C24H21O3 357.1491 found 357.1487.
6-(4-Methoxyphenyl)-1-methyl-3-(1-(p-tolyl)vinyl)quinolin-2(1H)-
one (4r). Chromatography on silica gel (AcOEt/Cyclohexane, 2/98 to
5/95) afforded 114 mg of 4r (0.31 mmol, yield 31%). Yellow solid, mp
150−151 °C. TLC Rf = 0.20 (AcOEt/Cyclohexane, 20/80, SiO2). IR
3-(1-(4-Isobutylphenyl)vinyl)-1,1-biphenyl (4l). Chromatography
on silica gel (Cyclohexane) afforded 274 mg of 4l (0.88 mmol, yield
88%). Yellow oil. TLC Rf = 0.51 (Cyclohexane, SiO2). IR (neat) 1597,
1
(neat) 1641 (CO stretch), 1567, 1496, 1247, 1181 cm−1. H NMR
(300 MHz, CDCl3) δ (ppm) 7.83−7.73 (m, 3H, HAr), 7.56 (d, J = 8.9
Hz, 2H, HAr), 7.41 (d, J = 8.7 Hz, 1H, HAr), 7.29 (d, J = 8.1 Hz, 2H, HAr),
7.14 (d, J = 7.9 Hz, 2H, HAr), 7.01 (d, J = 8.8 Hz, 2H, HAr), 5.69 (d, J =
1.5 Hz, 1H, CH), 5.64 (d, J = 1.5 Hz, 1H, CH), 3.87 (s, 3H,
Ar−OCH3), 3.75 (s, 3H, N−CH3), 2.35 (s, 3H, Ar−CH3). 13C{1H}
NMR (75 MHz, CDCl3) δ 161.3 (C), 159.4 (C), 146.1 (C), 138.9 (C),
137.9 (CH), 137.9 (C), 137.6 (C), 135.0 (C), 134.0 (C), 132.4 (C),
129.2 (2CH), 129.1 (CH), 128.0 (2CH), 126.8 (2CH), 126.4 (CH),
120.9 (C), 116.7 (CH2), 114.6 (3CH), 55.5 (CH3), 30.0 (CH3), 21.3
(CH3). HRMS (ESI) (M + H)+ m/z calcd for C26H24NO2 382.1807
found 382.1807.
1
1509, 1477, 1450, 1382, 1327 cm−1. H NMR (300 MHz, CDCl3) δ
(ppm) 7.60−7.52 (m, 4H, HAr), 7.48−7.38 (m, 3H, HAr), 7.38−7.27
(m, 4H, HAr), 7.12 (d, J = 8.2 Hz, 2H, HAr), 5.51 (d, J = 1.2 Hz, 1H, CH),
5.46 (d, J = 1.2 Hz, 1H, CH), 2.50 (d, J = 7.2 Hz, 2H, Ar−CH2), 1.97−
1.82 (m, 1H, CH−(CH3)2), 0.93 (d, J = 6.6 Hz, 6H, CH−(CH3)2).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 149.9 (C), 142.3 (C), 141.5
(C), 141.1 (C), 141.1 (C), 138.6 (C), 129.0 (2CH), 128.7 (2CH), 128.5
(CH), 127.9 (2CH), 127.4 (CH), 127.3 (CH), 127.2 (2CH), 127.2
(CH), 126.5 (CH), 113.8 (CH2), 45.2 (CH2), 30.2 (CH), 22.4 (2CH3).
HRMS (APCI) (M + H)+ m/z calcd for C24H25 313.1956 found
313.1955.
3-(1-(4-Methoxyphenyl)vinyl)-1,1-biphenyl (4m). Chromatography
on silica gel (DCM/Cyclohexane, 0/100 to 1/99) afforded 234 mg
of 4m (0.82 mmol, yield 82%). White solid, mp 68−70 °C. TLC Rf =
0.35 (Heptane, SiO2). IR (neat) 1603, 1509, 1246, 1178 cm−1. 1H NMR
(300 MHz, CDCl3) δ (ppm) 7.74−7.59 (m, 4H, HAr), 7.59−7.45 (m,
3H, HAr), 7.45−7.36 (m, 4H, HAr), 7.02−6.89 (m, 2H, HAr), 5.54 (d, J =
1.2 Hz, 1H, CH), 5.51 (d, J = 1.2 Hz, 1H, CH), 3.89 (s, 3H, Ar−
OCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 159.5 (C), 149.6 (C),
142.5 (C), 141.2 (2C), 134.0 (C), 129.5 (2CH), 128.9 (2CH), 128.7
(CH), 127.5 (CH), 127.4 (CH), 127.3 (2CH) 127.3 (CH), 126.6
(CH), 113.7 (CH2), 113.3 (2CH), 55.4 (CH3). HRMS (ESI) (M + H)+
m/z calcd for C21H19O 287.1436 found 287.1448.
2-(1-(3′,4′,5′-Trimethoxy-[1,1-biphenyl]-3-yl)vinyl)naphthalene
(4n). Chromatography on silica gel (DCM/Cyclohexane, 1/99 to 2/98)
afforded 250 mg of 4n (0.63 mmol, yield 63%). Yellow oil. TLC Rf = 0.23
(DCM/Cyclohexane, 10/90, SiO2). IR (neat) 1584, 1508, 1457, 1397,
1126 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.91−7.77 (m, 4H,
HAr), 7.62−7.33 (m, 7H, HAr), 6.80 (s, 2H), 5.69 (d, J = 1.0 Hz, 1H,
CH), 5.63 (d, J = 1.0 Hz, 1H, CH), 3.93 (s, 6H, 2 Ar−OCH3), 3.90
(s, 3H, Ar−OCH3). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 153.6
(2C), 150.1 (C), 142.3 (C), 141.6 (C), 138.8 (C), 137.9 (C), 137.2 (C),
133.5 (C), 133.2 (C), 128.8 (CH), 128.3 (CH), 127.9 (CH), 127.8
(CH), 127.7 (CH), 127.4 (CH), 127.3 (CH), 126.8 (CH), 126.4 (CH),
126.4 (CH), 126.3 (CH), 115.3 (CH2), 104.8 (2CH), 61.1 (CH3), 56.4
(2CH3). HRMS (ESI) (M + H)+ m/z calcd for C27H25O3 397.1804
found 397.1803.
3-(1-(4-Isobutylphenyl)vinyl)-1,1-biphenyl (4s). Chromatography
on silica gel (Cyclohexane) afforded 265 mg of 4s (0.85 mmol, yield
85%). Yellow oil. TLC Rf = 0.51 (Cyclohexane, SiO2). IR (neat) 1597,
1
1509, 1477, 1450, 1382, 1327 cm−1. H NMR (300 MHz, CDCl3) δ
(ppm) 7.60−7.52 (m, 4H, HAr), 7.48−7.38 (m, 3H, HAr), 7.38−7.27 (m,
4H, HAr), 7.12 (d, J = 8.2 Hz, 2H, HAr), 5.51 (d, J = 1.2 Hz, 1H, CH),
5.46 (d, J = 1.2 Hz, 1H, CH), 2.50 (d, J = 7.2 Hz, 2H, Ar−CH2), 1.97−
1.82 (m, 1H, CH−(CH3)2), 0.93 (d, J = 6.6 Hz, 6H, CH−(CH3)2).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 149.9 (C), 142.3 (C), 141.5
(C), 141.1 (C), 141.1 (C), 138.6 (C), 129.0 (2CH), 128.7 (2CH), 128.5
(CH), 127.9 (2CH), 127.4 (CH), 127.3 (CH), 127.2 (2CH), 127.2
(CH), 126.5 (CH), 113.8 (CH2), 45.2 (CH2), 30.2 (CH), 22.4 (2CH3).
HRMS (APCI) (M + H)+ m/z calcd for C24H25 313.1956 found 313.1955.
2-(1-(3,4-Dimethoxyphenyl)vinyl)-1,1-biphenyl (4t). Chromatog-
raphy on silica gel (EtOAc/Cyclohexane, 0/100 to 20/80) afforded
190 mg of 4t (0.60 mmol, yield 60%). White solid, mp 83−85 °C. TLC
Rf = 0.50 (AcOEt/Cyclohexane, 30/70, SiO2). IR (neat) 1579, 1510,
1
1462, 1318, 1225, 1135 cm−1. H NMR (300 MHz, CDCl3) δ (ppm)
7.47−7.30 (m, 4H, HAr), 7.24−7.10 (m, 5H, HAr), 6.66−6.60 (m, 3H,
HAr), 5.50 (d, J = 1.3 Hz, 1H, CH), 5.12 (d, J = 1.3 Hz, 1H, CH),
3.81 (s, 3H, Ar−OCH3), 3.74 (s, 3H, Ar−OCH3). 13C{1H} NMR (75
MHz, CDCl3) δ (ppm) 149.2 (C), 148.4 (C), 148.3 (C), 141.6 (C),
141.3 (C), 140.9 (C), 134.5 (C), 130.7 (CH), 130.1 (CH), 129.0
(2CH), 127.7 (CH), 127.6 (2CH), 127.0 (CH), 126.5 (CH), 112.0
(CH), 114.9 (CH2), 110.5 (CH), 110.4 (CH), 55.8 (CH3), 55.8 (CH3).
HRMS (ESI) (M + H)+ m/z calcd for C22H21O2 317.1542 found
317.1543.
5-(4-Methoxyphenyl)-1-methyl-3-(1-(p-tolyl)vinyl)-1H-indole
(4p). Chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to
20/70) afforded 96 mg of 4p (0.27 mmol, yield 27%). Yellow oil. TLC
Rf = 0.26 (AcOEt/Cyclohexane, 20/80, SiO2). IR (neat) 1550, 1505,
5-(4-(1-(4-Isobutylphenyl)vinyl)phenyl)-1-methyl-1H-indole (4u).
Chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to 2/98)
afforded 311 mg of 4u (0.85 mmol, yield 85%). Yellow solid, mp
I
DOI: 10.1021/acs.joc.5b00880
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
131−133 °C. TLC Rf = 0.31 (Cyclohexane, SiO2). IR (neat) 1604, 1509,
4-(2-Methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)pyridine
(4z). Chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to
30/70) afforded 322 mg of 4z (0.85 mmol, yield 85%). Yellow oil. TLC
Rf = 0.22 (AcOEt/Cyclohexane, 30/70, SiO2). IR (neat) 1578, 1504,
1
1482, 1420, 1336, 1245 cm−1. H NMR (300 MHz, CDCl3) δ (ppm)
7.90 (d, J = 1.2 Hz, 1H, HAr), 7.66 (d, J = 8.4 Hz, 2H, HAr), 7.54 (dd, J =
8.5, 1.7 Hz, 1H, HAr), 7.45 (d, J = 8.4 Hz, 2H, HAr), 7.41 (d, J = 8.5 Hz,
1H, HAr), 7.35 (d, J = 8.2 Hz, 2H, HAr), 7.16 (d, J = 8.2 Hz, 2H, HAr), 7.10
(d, J = 3.1 Hz, 1H, HAr), 6.57 (dd, J = 3.1, 0.6 Hz, 1H, HAr), 5.51 (d, J =
1.3 Hz, 1H, CH), 5.48 (d, J = 1.3 Hz, 1H, CH), 3.83 (s, 3H,
N−CH3), 2.54 (d, J = 7.2 Hz, 2H, Ar−CH2), 2.00−1.87 (m, 1H,
CH−(CH3)2), 0.97 (d, J = 6.6 Hz, 6H, CH−(CH3)2). 13C{1H} NMR
(75 MHz, CDCl3) δ (ppm) 149.9 (C), 1421 (C), 141.5 (C), 139.7 (C),
139.1 (C), 136.5 (C), 132.5 (C), 129.6 (CH), 129.1 (C), 129.1 (2CH),
128.7 (2CH), 128.2 (2CH), 127.1 (2CH), 121.4 (CH), 119.4 (CH),
113.4 (CH2), 109.6 (CH), 101.5 (CH), 45.3 (CH2), 33.1 (CH3), 30.4
(CH), 22.6 (2CH3). HRMS (APCI) (M + H)+ m/z calcd for C27H28N
366.2222 found 366.2220.
1
1411, 1345, 1235, 1125 cm−1. H NMR (300 MHz, CDCl3) δ (ppm)
8.62−8.60 (m, 2H, HAr), 7.46−7.44 (m, 2H, HAr), 7.40−7.35 (m, 2H,
HAr), 6.97 (d, J = 9.2 Hz, 1H, HAr), 6.57 (s, 2H, HAr), 5.41 (s, 1H, 
CH), 5.37 (s, 1H, CH), 3.88 (s, 3H, Ar−OCH3), 3.86 (s, 3H,
Ar−OCH3), 3.82 (s, 6H, 2Ar−OCH3). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 156.4 (C), 153.0 (2C) 149.5 (2CH), 149.1 (C), 146.1
(C), 138.0 (C), 137.1 (C), 134.2 (C), 130.3 (CH), 130.0 (CH), 127.4
(C), 124.3 (2CH), 113.1 (CH2), 111.1 (CH), 105.7 (2CH), 60.9
(CH3), 56.2 (2CH3), 55.7 (CH3). HRMS (ESI) (M + H)+ m/z calcd for
C23H24NO4 378.1705 found 378.1712.
5-(2-Methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)-1-
methyl-1H-pyrazole (4aa). Chromatography on silica gel (EtOAc/
Cyclohexane, 0/100 to 25/75) afforded 251 mg of 4aa (0.66 mmol,
yield 66%). Yellow oil. TLC Rf = 0.33 (AcOEt/Cyclohexane, 30/70,
5-(4-(1-(4-Fluorophenyl)vinyl)phenyl)-1-methyl-1H-pyrazole (4v).
Chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to 20/80)
afforded 197 mg of 4v (0.71 mmol, yield 71%). White solid, mp
77−78 °C. TLC Rf = 0.59 (AcOEt/Cyclohexane, 50/50, SiO2). IR
1
SiO2). IR (neat) 1579, 1503, 1462, 1411, 1342, 1251, 1126 cm−1. H
NMR (300 MHz, CDCl3) δ (ppm) 7.50 (d, J = 1.9 Hz, 1H, HHet), 7.40
(dd, J = 8.6, 2.4 Hz, 1H, HAr), 7.27 (d, J = 2.3 Hz, 1H, HAr), 6.95 (d, J =
8.6 Hz, 1H, HAr), 6.55 (s, 2H, HAr), 6.22 (d, J = 1.9 Hz, 1H, HHet), 5.40
(d, J = 1.1 Hz, 1H, CH), 5.35 (d, J = 1.1 Hz, 1H, CH), 3.87 (s, 3H,
Ar−OCH3), 3.84 (s, 3H, Ar−OCH3), 3.81 (s, 6H, 2Ar−OCH3), 3.73 (s,
3H, N−CH3). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 156.8 (C),
153.0 (2C), 149.0 (C), 140.1 (C), 138.4 (CH), 138.1 (C), 137.2 (C),
133.8 (C), 131.4 (CH), 130.3 (CH), 119.6 (C), 113.2 (CH2), 110.8
(CH), 106.9 (CH), 105.8 (2CH), 61.0 (CH3), 56.3 (2CH3), 55.7
(CH3), 37.3 (CH3). HRMS (ESI) (M + H)+ m/z calcd for C22H25N2O4
381.1814 found 381.1812.
1
(neat) 1601, 1507, 1224, 1159 cm−1. H NMR (300 MHz, CDCl3) δ
(ppm) 7.52 (d, J = 1.9 Hz, 1H, HHet), 7.40 (s, 4H, HAr), 7.33 (dd, J = 8.8,
5.4 Hz, 2H, HAr), 7.05 (t, J = 8.7 Hz, 2H, HAr), 6.33 (d, J = 1.9 Hz, 1H,
H
Het), 5.51 (s, 1H, CH), 5.47 (s, 1H, CH), 3.93 (s, 3H, N−CH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 162.8 (C, d, J = 245.3 Hz),
148.5 (C), 143.3 (C), 141.5 (C), 138.7 (CH), 137.3 (C, d, J = 3.0 Hz),
130.4 (C), 130.1 (2CH, d, J = 8.3 Hz), 128.7 (2CH), 128.5 (2CH),
115.3 (2CH, d, J = 21.0 Hz), 115.0 (CH2), 106.3 (CH), 37.7 (CH3).
HRMS (ESI) (M + H)+ m/z calcd for C18H16FN2 279,1298 found
279.1301.
(E)-1-(3-Methoxyprop-1-en-1-yl)-4-(1-(p-tolyl)vinyl)benzene (4w).
Chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to 10/90)
afforded 182 mg of 4w (0.69 mmol, yield 69%). Yellow oil. TLC Rf =
0.37 (AcOEt/Cyclohexane, 20/80, SiO2). IR (neat) 1508, 1457, 1379,
1184, 1119 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.39 (d, J = 8.4
Hz, 2H, HAr), 7.33 (d, J = 8.5 Hz, 2H, HAr), 7.27 (d, J = 8.0 Hz, 2H, HAr),
7.18 (d, J = 7.9 Hz, 2H, HAr), 6.66 (d, J = 16.0 Hz, 1H, CH), 6.33 (dt,
J = 15.9, 6.0 Hz, 1H, CH), 5.46 (d, J = 1.2 Hz, 1H, CH), 5.44 (d, J =
1.2 Hz, 1H, CH), 4.14 (dd, J = 6.0, 1.4 Hz, 2H, CH2−OCH3), 3.43
(s, 3H, OCH3), 2.40 (s, 3H, Ar−CH3). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 149.6 (C), 141.1 (C), 138.7 (C), 137.7 (C), 136.3 (C),
132.2 (2CH), 129.0 (2CH), 128.6 (2CH), 128.3 (2CH), 126.4 (2CH),
126.2 (CH), 113.7 (CH2), 73.2 (CH2), 58.1 (CH3), 21.3 (CH3). HRMS
(APCI) (M + H)+ m/z calcd for C19H21O 265,1592 found 265.1613.
(E)-1-Methyl-4-(1-(4-styrylphenyl)vinyl)benzene (4x). Chromatog-
raphy on silica gel (Cyclohexane) afforded 155 mg of 4x (0.52 mmol,
yield 52%). White solid, mp 144−146 °C. TLC Rf = 0.43 (Cyclohexane,
(E)-5-(1-(3-(2-Cyclopropylvinyl)-4-methoxyphenyl)vinyl)-1,2,3-tri-
methoxybenzene (4ab). Chromatography on silica gel (EtOAc/
Cyclohexane, 0/100 to 20/80) afforded 223 mg of 4ab (0.61 mmol,
yield 61%). Yellow oil. TLC Rf = 0.73 (AcOEt/Cyclohexane, 30/70,
1
SiO2). IR (neat) 1582, 1499, 1461, 1412, 1331, 1246, 1126 cm−1. H
NMR (300 MHz, CDCl3) δ (ppm) 7.37 (d, J = 2.2 Hz, 1H, HAr), 7.12
(dd, J = 8.5, 2.3 Hz, 1H, HAr), 6.82−6.75 (m, 2H, HAr + CH), 6.56 (s,
2H, HAr), 5.72 (dd, J = 15.9, 8.9 Hz, 1H, CH), 5.36 (d, J = 1.3 Hz, 1H,
CH), 5.33 (d, J = 1.3 Hz, 1H, CH), 3.88 (s, 3H, Ar−OCH3), 3.87
(s, 3H, Ar−OCH3), 3.81 (s, 6H, 2Ar−OCH3), 1.66−1.51 (m, 1H, CH−
(CH2)2), 0.85−0.76 (m, 2H, CH−(CH2)2), 0.54−0.46 (m, 2H, CH−
(CH2)2). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 156.1 (C), 153.0
(2C), 149.9 (C), 137.9 (C), 137.6 (C), 136.2 (CH), 133.8 (C), 127.8
(CH), 126.6 (C), 126.3 (CH), 122.0 (CH), 112.7 (CH2), 110.5 (CH),
105.8 (2CH), 61.2 (CH3), 56.3 (2CH3), 55.7 (CH3), 15.2 (CH), 7.5
(2CH2). HRMS (ESI) (M + H)+ m/z calcd for C23H27O4 367.1909
found 367.1913.
1
SiO2). IR (neat) 1604, 1509, 1446, 1327, 1264 cm−1. H NMR (300
(E)-1,2,3-Trimethoxy-5-(1-(4-methoxy-3-styrylphenyl)vinyl)-
benzene (4ac). Chromatography on silica gel (EtOAc/Cyclohexane,
0/100 to 20/80) afforded 191 mg of 4ac (0.47 mmol, yield 47%). Yellow
oil. TLC Rf = 0.42 (AcOEt/Cyclohexane, 30/70, SiO2). IR (neat) 1579,
MHz, CDCl3) δ (ppm) 7.60−7.47 (m, 4H, HAr), 7.44−7.34 (m, 4H,
HAr), 7.34−7.25 (m, 3H, HAr), 7.23−7.14 (m, 4H, HAr), 5.49 (d, J = 1.3
Hz, 1H, CH), 5.46 (d, J = 1.2 Hz, 1H, CH), 2.41 (s, 3H, Ar−CH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 149.7 (C), 141.1 (C), 138.7
(C), 137.7 (C), 137.5 (C), 136.9 (C), 129.0 (2CH), 128.9 (CH), 128.8
(2CH), 128.7 (2CH), 128.4 (CH), 128.4 (2CH), 127.8 (CH), 126.7
(2CH), 126.4 (2CH), 113.7 (CH2), 21.3 (CH3). HRMS (APCI)
(M + H)+ m/z calcd for C23H21 297.1643 found 297.1640.
1
1505, 1456, 1338, 1248, 1127 cm−1. H NMR (300 MHz, CDCl3) δ
(ppm) 7.64 (d, J = 2.2 Hz, 1H, HAr), 7.59−7.47 (m, 3H, HAr), 7.39−7.34
(m, 2H, HAr), 7.29−7.23 (m, 2H, HAr), 7.13 (d, J = 16.5 Hz, 1H, CH),
6.90 (d, J = 8.6 Hz, 1H, HAr), 6.62 (s, 2H, HAr), 5.45 (d, J = 1.2 Hz,
1H, CH), 5.41 (d, J = 1.2 Hz, 1H, CH), 3.94 (s, 3H, Ar−OCH3),
3.92 (s, 3H, Ar−OCH3), 3.85 (s, 6H, 2Ar−OCH3). 13C{1H} NMR (75
MHz, CDCl3) δ 156.9 (C), 153.0 (2C), 149.7 (C), 138.0 (C), 138.0
(C), 137.5 (C), 133.9 (C), 129.6 (CH), 128.9 (CH), 128.7 (2CH),
127.6 (CH), 126.7 (2CH), 126.5 (CH), 126.2 (C), 123.5(C), 112.9
(CH2), 110.7 (CH), 105.8 (2CH), 61.1 (CH3), 56.3 (2CH3), 55.8
(CH3). HRMS (ESI) (M + H)+ m/z calcd for C26H27O4 403.1909 found
403.1909.
2-Methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)-1,1-biphenyl (4y).
Chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to 20/80)
afforded 172 mg of 4y (0.46 mmol, yield 46%). Yellow oil. TLC Rf = 0.61
(AcOEt/Cyclohexane, 30/70, SiO2). IR (neat) 1578, 1504, 1410, 1342,
1
1233, 1124 cm−1. H NMR (300 MHz, CDCl3) δ (ppm) 7.57−7.50
(m, 2H, HAr), 7.50−7.29 (m, 5H, HAr), 6.98 (d, J = 8.5 Hz, 1H, HAr),
6.64 (s, 2H, HAr), 5.46 (d, J = 1.2 Hz, 1H, CH), 5.39 (d, J = 1.2 Hz,
1H, CH), 3.92 (s, 3H, Ar−OCH3), 3.85 (s, 9H, 3Ar−OCH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 156.4 (C), 152.9 (2C),
149.5 (C), 138.3 (C), 137.9 (C), 137.5 (C), 133.8 (C), 130.8 (CH),
130.4 (C), 129.6 (2CH), 128.5 (CH), 128.0 (2CH), 127.1 (CH), 112.8
(CH2), 110.9 (CH), 105.7 (2CH), 60.9 (CH3), 56.2 (2CH3), 55.7
(CH3). HRMS (ESI) (M + H)+ m/z calcd for C24H25O4 377.1753 found
377.1756.
(E)-1,2,3-Trimethoxy-5-(1-(4-methoxy-3-(3-methoxyprop-1-en-1-
yl)phenyl)vinyl)benzene (4ad). Chromatography on silica gel (EtOAc/
Cyclohexane, 0/100 to 20/80) afforded 171 mg of 4ad (0.46 mmol,
yield 46%). Yellow oil. TLC Rf = 0.65 (AcOEt/Cyclohexane, 30/70,
1
SiO2). IR (neat) 1584, 1499, 1456, 1412, 1331, 1247, 1125 cm−1. H
NMR (300 MHz, CDCl3) δ (ppm) 7.46 (d, J = 2.3 Hz, 1H, HAr), 7.21
(dd, J = 8.5, 2.3 Hz, 1H, HAr), 6.91 (d, J = 16.1 Hz, 1H, CH), 6.83
J
DOI: 10.1021/acs.joc.5b00880
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The Journal of Organic Chemistry
Article
(d, J = 8.6 Hz, 1H, HAr), 6.55 (s, 2H, HAr), 6.28 (dt, J = 16.1, 6.1 Hz, 1H,
CH), 5.37 (d, J = 1.2 Hz, 1H, CH), 5.33 (d, J = 1.2 Hz, 1H, CH),
4.09 (dd, J = 6.1, 1.4 Hz, 2H, CH2−OCH3), 3.88 (s, 3H, Ar−OCH3),
3.87 (s, 3H, Ar−OCH3), 3.81 (s, 6H, 2Ar−OCH3), 3.38 (s, 3H, CH2−
OCH3). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm) 156.8 (C), 153.0
(2C), 149.7 (C), 137.9 (C), 137.5 (C), 133.8 (C), 128.9 (CH), 127.5
(CH), 127.2 (2CH), 125.5 (C), 112.8 (CH2), 110.6 (CH), 105.7
(2CH), 73.7 (CH2), 61.0 (CH3), 58.1 (CH3), 56.3 (2CH3), 55.7 (CH3).
HRMS (ESI) (M + H)+ m/z calcd for C22H27O5 371.1858 found
371.1858.
(E)-tert-Butyl((3-(2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)-
phenyl)allyl)oxy)dimethylsilane (4ae). Chromatography on silica gel
(EtOAc/Cyclohexane, 0/100 to 20/80) afforded 301 mg of 4ae
(0.64 mmol, yield 64%). Yellow oil. TLC Rf = 0.43 (AcOEt/
Cyclohexane, 10/90, SiO2). IR (neat) 1583, 1501, 1462, 1332, 1255,
1126 cm−1. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.45 (d, J = 2.3 Hz,
1H, HAr), 7.19 (dd, J = 8.5, 2.3 Hz, 1H, HAr), 6.90 (dt, J = 15.9, 1.6 Hz,
1H, CH), 6.82 (d, J = 8.5 Hz, 1H, HAr), 6.57 (s, 2H, HAr), 6.28 (dt,
J = 16.0, 5.2 Hz, 1H, CH), 5.38 (d, J = 1.2 Hz, 1H, CH), 5.34 (d, J =
1.2 Hz, 1H, CH), 4.35 (dd, J = 5.2, 1.7 Hz, 2H,, CH2−OCH3), 3.88 (s,
3H, Ar−OCH3), 3.86 (s, 3H, Ar−OCH3), 3.81 (s, 6H, 2Ar−OCH3),
0.94 (s, 9H, tBu), 0.10 (s, 6H, Si−(CH3)2). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 156.7 (C), 153.0 (2C), 149.8 (C), 138.0 (C), 137.6
(C), 133.8 (C), 130.4 (CH), 128.5 (CH), 127.1 (CH), 126.0 (C), 124.6
(CH), 112.7 (CH2), 110.6 (CH), 105.8 (2CH), 64.5 (CH2), 61.0
(CH3), 56.3 (2CH3), 55.7 (CH3), 26.1 (3CH3), 18.6 (C), −5.0 (2CH3).
HRMS (ESI) (M + Na)+ m/z calcd for C27H38NaO5Si 493.2386 found
493.2390.
silica gel (EtOAc/Cyclohexane, 2/98 to 10/90) as a yellow solid (yield:
1.40 g, 3.8 mmol, 94%). The spectroscopic data were in full accord with
those reported previously. TLC Rf = 0.53 (EtOAC/Cyclohexane, 20/80,
SiO2). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.85 (s, 1H, HAr), 6.73
(s, 1H, HAr), 5.22 (s, 2H, O−CH2−O), 3.87 (s, 3H, Ar−OCH3), 3.51
(s, 3H, OCH3).
(E)-5-(Prop-1-en-1-yl)benzofuran (9). 5-Bromobenzofuran 8 (5 mmol,
985 mg), potassium trans-1-propenyltrifluoroborate (5.25 mmol, 772 mg),
PdCl2(dppf).CH2Cl2 (0.1 mmol, 82 mg) and tBuNH2 (15.75 mmol, 1.7 mL)
were dissolved in iPrOH/H2O (50 mL, 2/1, v/v). The resulting mixture
was stirred at reflux under an argon atmosphere for 4 h. The mixture was
cooled to room temperature and diluted with water (100 mL), followed
by extraction with diethyl ether. Organic layers were combined and
washed with HCl (1 N) and brine, dried over MgSO4 and concentrated
in vacuo. The product was isolated by chromatography on silica gel
(Cyclohexane) as a colorless liquid (yield: 698 mg, 4.4 mmol, 88%).
TLC Rf = 0.60 (Cyclohexane, SiO2). IR (neat) 1597, 1509, 1477, 1450,
1382, 1327. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.59 (d, J = 2.2 Hz,
1H, HAr), 7.52 (d, J = 1.6 Hz, 1H, HAr), 7.41 (d, J = 8.6 Hz, 1H, HAr), 7.31
(dd, J = 8.6, 1.7 Hz, 1H, HAr), 6.73 (dd, J = 2.2, 0.9 Hz, 1H, HAr), 6.49
(dq, J = 15.7, 1.6 Hz, 1H, CH), 6.20 (dq, J = 15.7, 6.6 Hz, 1H, CH),
1.90 (dd, J = 6.6, 1.6 Hz, 3H, CH−CH3). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 154.2 (C), 145.3 (CH), 133.1 (C), 131.0 (CH), 127.7
(C), 124.5 (CH), 122.4 (CH), 118.3 (CH), 111.2 (CH), 106.6 (CH),
18.5 (CH3). HRMS (APCI) (M + H)+ m/z calcd for C11H11O 159.0810
found 159.0810.
(E)-4,4,5,5-Tetramethyl-2-(5-(prop-1-en-1-yl)benzofuran-2-yl)-
1,3,2-dioxaborolane (5k). To a flask under argon, containing
[Ir(OMe)(cod)]2 (0.03 mmol, 20 mg), 4,4′-di-tert-butyl-2,2′-bipyridine
(0.06 mmol, 16 mg) and bis(pinacolato)diboron (1 mmol, 254 mg) was
added degassed n-hexane (6 mL) and (E)-5-(prop-1-en-1-yl)-
benzofuran 9 (2 mmol, 316 mg). The resulting mixture was stirred at
50 °C under an argon atmosphere for 3 h. The crude product was
isolated by filtration on silica gel with EtOAc/Cyclohaxane (200 mL,
7/3, v/v) as a brown oil and used without further purification in the next
step. TLC Rf = 0.53 (EtOAc/Cyclohexane, 20/80, SiO2). 1H NMR (300
MHz, CDCl3) δ (ppm) 7.55 (d, J = 1.5 Hz, 1H, HAr), 7.48 (d, J = 8.6 Hz,
1H, HAr), 7.42−7.34 (m, 2H, HAr), 6.50 (dq, J = 15.7, 1.6 Hz, 1H, 
CH), 6.21 (dq, J = 15.7, 6.6 Hz, 1H, CH), 1.90 (dd, J = 6.6, 1.6 Hz,
3H, CH−CH3), 1.40 (s, 12H, 6CH3).
(E)-3-(2-Methoxy-5-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)-
prop-2-en-1-ol (4af). To a solution of 4ae (246 mg, 0.5 mmol) in 5 mL
of THF is added TBAF (1.0 M in THF) (1 mL, 1 mmol) at 0 °C. The
resulting mixture is stirred 2h at room temperature. Solvents are
removed under reduce pressure and the crude mixture is purified by
chromatography. Chromatography on silica gel (DCM/Cyclohexane,
0/100 to 20/80) afforded 146 mg of 4af (0.41 mmol, yield 82%).
Colorless oil. TLC Rf = 0.20 (AcOEt/Cyclohexane, 20/80, SiO2). IR
1
(neat) 1580, 1504, 1456, 1411, 1338, 1240, 1126 cm−1. H NMR
(300 MHz, CDCl3) δ (ppm) 7.45 (d, J = 2.2 Hz, 1H, HAr), 7.21 (dd, J =
8.5, 2.3 Hz, 1H, HAr), 6.91 (d, J = 16.1 Hz, 1H, CH), 6.84 (d, J = 8.5
Hz, 1H, HAr), 6.55 (s, 2H, HAr), 6.37 (dt, J = 16.0, 5.8 Hz, 1H, CH),
5.37 (d, J = 1.2 Hz, 1H, CH), 5.34 (d, J = 1.2 Hz, 1H, CH), 4.32 (d,
J = 5.1 Hz, 2H, CH2−OCH3), 3.88 (s, 3H, Ar−OCH3), 3.88 (s, 3H,
Ar−OCH3), 3.81 (s, 6H, 2Ar−OCH3). 13C{1H} NMR (75 MHz,
CDCl3) δ (ppm) 156.6 (C), 152.9 (2C), 149.5 (C), 137.8 (C), 137.4
(C), 133.7 (C), 129.7 (CH), 128.8 (CH), 127.0 (CH), 126.0 (CH),
125.3 (C), 112.7 (CH2), 110.4 (CH), 105.6 (2CH), 64.1 (CH2), 60.9
(CH3), 56.2 (2CH3), 55.6 (CH3). HRMS (ESI) (M + Na)+ m/z calcd
for C21H25O5Na 379.1521 found 379.1523.
1-(5-Bromo-2-((4-methoxybenzyl)oxy)phenyl)ethanone (11).
1-(5-Bromo-2-hydroxyphenyl)ethanone 1a (15 mmol, 3.23 g) was
dissolved in acetone (50 mL), then K2CO3 (45 mmol, 6.21 g), KI
(15 mmol, 2.49 g) and PMBCl (30 mmol, 4.1 mL) were added at RT.
The resulting mixture was stirred at reflux overnight. The mixture was
cooled to RT, filtered and concentrated in vacuo. The product was
isolated by chromatography on silica gel (EtOAc/Cyclohexane, 2/98 to
10/90) as a white solid (yield: 4.99 g, 14.9 mmol, 99%). TLC Rf = 0.60
(EtOAC/Cyclohexane, 20/80, SiO2). IR (neat) 1671, 1514, 1395, 1249,
1173. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.84 (d, J = 2.6 Hz, 1H,
HAr), 7.52 (dd, J = 8.8, 2.6 Hz, 1H, HAr), 7.34 (d, J = 8.8 Hz, 2H, HAr),
6.95−6.88 (m, 3H, HAr), 5.07 (s, 2H, Ar−OCH2−Ar), 3.83 (s, 3H
Ar−OCH3), 2.55 (s, 3H, CO−CH3). 13C{1H} NMR (75 MHz, CDCl3)
δ (ppm) 198.4 (C), 159.9 (C), 157.2 (C), 136.1 (CH), 133.2 (CH),
130.3 (C), 129.5 (2CH), 127.8 (C), 115.0 (CH), 114.3 (2CH), 113.5
(C), 71.0 (CH2), 55.5 (CH3), 32.1 (CH3). HRMS (ESI) (M + Na)+ m/z
calcd for C16H15BrO3Na 357,0102 found 357.0094.
(E)-1-(2-((4-Methoxybenzyl)oxy)-5-(prop-1-en-1-yl)phenyl)-
ethanone (12). 1-(5-Bromo-2-((4-methoxybenzyl)oxy)phenyl)-
ethanone 11 (5 mmol, 1.68 g), potassium trans-1-propenyltrifluor-
oborate (5.25 mmol, 772 mg), PdCl2(dppf).CH2Cl2 (0.1 mmol, 82 mg)
and tBuNH2 (15.75 mmol, 1.7 mL) were dissolved in iPrOH/H2O
(50 mL, 2/1, v/v). The resulting mixture was stirred at reflux under an
argon atmosphere for 4 h. The mixture was cooled to room temperature
and diluted with water (100 mL), followed by extraction with diethyl
ether. Organic layers were combined and washed with HCl (1 N) and
brine, dried over MgSO4 and concentrated in vacuo. The product was
isolated by chromatography on silica gel (EtOAc/Cyclohexane, 2/98 to
10/90) as a white solid (yield: 1.43 g, 4.8 mmol, 97%). TLC Rf = 0.60
(EtOAC/Cyclohexane, 20/80, SiO2). IR (neat) 1668, 1515, 1494, 1407,
1-Bromo-5-iodo-2-methoxy-4-(methoxymethoxy)benzene (2i).
2-Iodo-5-methoxyphenol (6) (4 mmol, 1.00 g) and potassium carbonate
(12 mmol, 1.67g) were dissolved in acetone (20 mL), and then
chloromethyl methyl ether (8 mmol, 0.61 mL) was added at RT. The
resulting mixture was stirred at reflux for 3 h. The mixture was cooled to
RT, and potassium carbonate was filtered off. The filtrate was con-
centrated in vacuo. The crude 1-iodo-4-methoxy-2-(methoxymethoxy)-
benzene (7) was used in the next reaction without further purification.
The spectroscopic data were in full accord with those reported
1
previously. TLC Rf = 0.51 (EtOAC/Cyclohexane, 20/80, SiO2). H
NMR (300 MHz, CDCl3) δ (ppm) 7.62 (d, J = 8.7 Hz, 1H, HAr), 6.69 (d,
J = 2.7 Hz, 1H, HAr), 6.38 (dd, J = 8.7, 2.7 Hz, 1H, HAr), 5.22 (s, 2H,
O−CH2−O), 3.78 (s, 3H, Ar−OCH3), 3.51 (s, 3H, OCH3). To a
solution of the crude 1-iodo-4-methoxy-2-(methoxymethoxy)benzene
(7) in acetonitrile (20 mL) were added silica gel (300 mg), butylated
hydroxytoluene (14 mg), and N-bromosuccinimide (4 mmol, 712 mg).
The resulting mixture was stirred at RT for 1 h. The mixture was filtered
and the filtrate was concentrated in vacuo. The residue was dissolved in
CH2Cl2/H2O (100 mL, 1/1, v/v) and vigorously stirred for 5 min. The
layers were then separated and the aqueous phase was extracted twice
with CH2Cl2. Organic layers were combined, dried over MgSO4 and
concentrated in vacuo. The product was isolated by chromatography on
K
DOI: 10.1021/acs.joc.5b00880
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1243. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.70 (d, J = 2.4 Hz, 1H,
HAr), 7.40 (dd, J = 8.6, 2.4 Hz, 1H, HAr), 7.35 (d, J = 8.7 Hz, 2H, HAr),
6.96 (d, J = 8.7 Hz, 1H, HAr), 6.92 (d, J = 8.7 Hz, 2H, HAr), 6.40−6.28
(m, 1H, CH), 6.15 (dq, J = 15.7, 6.4 Hz, 1H, CH), 5.07 (s, 2H, Ar−
OCH2−Ar), 3.82 (s, 3H Ar−OCH3), 2.56 (s, 3H, CO−CH3), 1.86 (dd,
J = 6.5, 1.5 Hz, 3H, CH−CH3). 13C{1H} NMR (75 MHz, CDCl3) δ
200.1 (C), 159.6 (C), 157.0 (C), 130.9 (C), 130.7 (CH), 129.5 (CH),
129.3 (2CH), 128.6 (C), 128.2 (C), 127.7 (CH), 125.0 (CH), 114.1
(2CH), 113.0 (CH), 70.6 (CH2), 55.3 (CH3), 32.1 (CH3), 18.4 (CH3).
HRMS (ESI) (M + Na)+ m/z calcd for C19H20O3Na 319.1310 found
319.1314.
maintained at 37 °C in a humidified atmosphere containing 5% CO2. All
cell lines were maintained at 37 °C in a humidified atmosphere
containing 5% CO2. Cell viability was assessed using Promega CellTiter-
Blue reagent according to the manufacturer’s instructions. Cells were
seeded in 96-well plates (5 × 103 cells/well) containing 50 μL growth
medium. After 24 h of culture, the cells were supplemented with 50 μL
of the tested compound dissolved in DMSO (less than 0.1% in each
preparation). After 72 h of incubation, 20 μL of resazurin was added for
2 h before recording fluorescence (λex = 560 nm, λem = 590 nm) using a
Victor microtiter plate fluorimeter (PerkinElmer, USA). The GI50
corresponds to the concentration of the tested compound that caused
a decrease of 50% in fluorescence of drug treated cells compared with
untreated cells. Experiments were performed in triplicate. The GI50
values for all compounds were compared to the GI50 of isoCA-4 and
measured the same day under the same conditions.
N′-(1-(2-((4-Methoxybenzyl)oxy)-5-((E)-prop-1-en-1-yl)phenyl)-
ethylidene)-4-methylbenzenesulfonohydrazide (1u). (E)-1-(2-((4-
Methoxybenzyl)oxy)-5-(prop-1-en-1-yl)phenyl)ethanone (12) (3.5 mmol,
1.04 g) was dissolved in ethanol (10 mL), then para-toluenesulfonylhy-
drazide (4.2 mmol, 0.78 g) was added at RT. The resulting mixture was
stirred at reflux for 1 h. The mixture was cooled to RT and the product
was isolated by filtration as a white solid (yield: 1.39 g, 3.0 mmol, 86%).
TLC Rf = 0.38 (EtOAC/Cyclohexane, 20/80, SiO2). IR (neat) 1613,
ASSOCIATED CONTENT
■
S
* Supporting Information
1515, 1493, 1340, 1237, 1166. H NMR (300 MHz, CD3COCD3) δ
Copies of 1H and 13C NMR spectra for all new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00880.
1
(ppm) 7.81 (d, J = 8.3 Hz, 2H, HAr), 7.42−7.32 (m, 4H, HAr), 7.30 (dd,
J = 8.6, 2.4 Hz, 1H, HAr), 7.13 (d, J = 2.3 Hz, 1H, HAr), 7.03 (d, J = 8.5 Hz,
1H, HAr), 6.96−6.86 (m, 2H, HAr), 6.33 (dq, J = 15.8, 1.6 Hz, 1H,
CH), 6.08 (dq, J = 15.7, 6.6 Hz, 1H, CH), 5.01 (s, 2H Ar−OCH2−Ar),
3.80 (s, 3H, Ar−OCH3), 2.85 (bs, 1H, NH), 2.41 (s, 3H, CN−CH3),
2.15 (s, 3H, Ar−CH3), 1.85 (dd, J = 6.6, 1.6 Hz, 3H, CH−CH3).
13C{1H} NMR (75 MHz, CD3COCD3) δ (ppm) 159.6 (C), 155.7 (C),
AUTHOR INFORMATION
■
Corresponding Authors
*Tel.: (+33) 1 4683-5498. Fax: (+33) 1 4683-5827. E-mail:
mouad.alami@u-psud.fr.
*E-mail: abdallah.hamze@u-psud.fr.
Notes
155.1 (C), 143.5 (C), 136.7 (C), 130.6 (C), 130.1 (CH), 129.4 (2CH),
129.2 (2CH), 129.1 (C), 128.9 (C), 128.1 (2CH), 127.6 (CH), 126.8
(CH), 123.6 (CH), 113.8 (2CH), 112.8 (2CH), 70.0 (CH2), 54.6
(CH3), 20.6 (CH3), 17.6 (CH3), 17.1 (CH3). HRMS (ESI) (M + Na)+
m/z calcd for C26H28N2O4SNa 487.1667 found 487.1666.
The authors declare no competing financial interest.
2-(2-Methoxy-5-(1-(2-((4-methoxybenzyl)oxy)-5-((E)-prop-1-en-1-
yl)phenyl)vinyl)-4-(methoxymethoxy)phenyl)-5-((E)-prop-1-en-1-yl)-
benzofuran (4ah). A round-bottom flask with condenser under argon,
was charged with N′-(1-(2-((4-methoxybenzyl)oxy)-5-((E)-prop-1-en-
1-yl)phenyl)ethylidene)-4-methylbenzenesulfonohydrazide 1u (1.1 mmol,
512 mg), 1-bromo-5-iodo-2-methoxy-4-(methoxymethoxy)benzene 2i
(1 mmol 373 mg), Pd(OAc)2 (0.04 mmol, 9 mg), Sphos (0.08 mmol
32 mg), lithium-tert-butoxide (2.4 mmol, 192 mg), and degassed
dioxane (6 mL). The resulting mixture was stirred at reflux for 2 h. Then,
potassium hydroxide (3 mmol, 168 mg), degassed water (50 mmol, 0.8 mL),
and crude (E)-4,4,5,5-tetramethyl-2-(5-(prop-1-en-1-yl)benzofuran-2-yl)-
1,3,2-dioxaborolane 5k (∼2 mmol) dissolved in degassed dioxane
(0.5 mL) were added and reflux was continued for 4 h. The mixture was
cooled to room temperature, diluted with EtOAc, filtered through
Celite, and concentrated in vacuo. The product was isolated by
chromatography on silica gel (EtOAc/Cyclohexane, 0/100 to 5/95) as a
white solid (yield: 2726 mg, 45%). TLC Rf = 0.48 (EtOAC/
Cyclohexane, 20/80, SiO2). IR (neat) 1514, 1464, 1302, 1216, 1082.
1H NMR (300 MHz, CDCl3) δ (ppm) 7.93 (s, 1H, HAr), 7.51 (d, J = 1.4
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support of this project by CNRS,
University Paris Sud, and by La Ligue Contre le Cancer
throughout an Equipe Labellisee 2014 grant. The BioCIS UMR
8076 laboratory is a member of the Laboratory of Excellence
LERMIT supported by a grant from ANR (ANR-10-LABX-33).
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